The present invention relates to the use of certain tetrahydropyridines for the preparation of drugs intended for the treatment of diseases which cause destruction of myelin.
These pathological conditions share the characteristic of being of inflammatory or autoimmune origin and of causing loss of myelin in the central nervous system. It is possible to draw a distinction principally between chronic pathological conditions, such as multiple sclerosis, and acute pathological conditions, such as acute disseminated encephalomyelitis and acute hemorrhagic leukoencephalitis. Among these pathological conditions, multiple sclerosis is the most widespread and leads to very serious sensory and visual motor dysfunctions.
No effective therapy is currently available for these diseases, and the treatments are limited to symptomatic treatments aimed at improving spastic hypertonia, fatigue and pain, or, since the origin of these pathological conditions is often said to be autoimmune, symptomatic treatments aimed at suppressing the immunological response.
WO 93/11107 describes a class of N-hydroxyalkyl-1,2,3,6-tetrahydropyridines as protectors against the damage caused by hypoxia.
EP 0 101 381 describes trifluoromethylphenyltetrahydropyridine derivatives having an anorexigenic activity and EP 0 458 696 describes their neuroprotective effects.
WO 97/01536 describes 1-phenylalkyl-1,2,3,6-tetrahydropyridines also having a neurotrophic and neuroprotective activity.
It has now been found that certain tetrahydropyridines exert a beneficial action on diseases which cause destruction of myelin.
Thus the present invention relates to the use of a compound of formula (I): 
in which:
R1 is a halogen or a CF3, (C1-C4)alkyl or (C1-C4)alkoxy group;
Y is a nitrogen atom or a CH group;
Zxe2x80x2 and Zxe2x80x3 are each hydrogen or a (C1-C3)alkyl group, or one is hydrogen and the other is a hydroxyl group, or the two together are an oxo group; and
Z is:
a phenyl radical;
a phenyl radical monosubstituted by a substituent X, X being:
(a) a (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)carboxyalkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C7)carboxyalkoxy or (C1-C4)alkoxycarbonyl(C1-C6)alkoxy group;
(b) a group selected from (C3-C7)cycloalkyl, (C3-C7)cycloalkoxy, (C3-C7)cycloalkylmethyl, (C3-C7)cycloalkylamino and cyclohexenyl, it being possible for said group to be substituted by a halogen, hydroxyl, (C1-C4)alkoxy, carboxyl, (C1-C4)alkoxycarbonyl, amino or mono- or di-(C1-C4)alkylamino; or
(c) a group selected from phenyl, phenoxy, phenylamino, Nxe2x80x94(C1-C3)alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, it being possible for said group to be monosubstituted or polysubstituted on the phenyl group by a halogen, CF3, (C1-C4)alkyl, (C1-C4)alkoxy, cyano, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)acylamino, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4)alkylaminocarbonyl, amino(C1-C4)alkyl, hydroxy(C1-C4)alkyl or halogeno(C1-C4)alkyl;
a phenyl radical disubstituted by a substituent R2, R2 being a halogen or a hydroxyl, methyl, ethyl, (C3-C6)alkyl, (C1-C4)alkoxy or trifluoromethyl group, and by a substituent X, X being as defined above;
a 1-naphthyl or 2-naphthyl radical; or
a 1-naphthyl or 2-naphthyl radical substituted in the 5-, 6-, 7- and/or 8-positions by one or two hydroxyl groups, one or two (C1-C4)alkoxy groups or a 6,7-methylenedioxy group;
or Zxe2x80x3 is hydrogen and Z and Zxe2x80x2 are each independently an unsubstituted or mono-, di- or tri-substituted phenyl group,
or one of its pharmaceutically acceptable salts and solvates, for the preparation of pharmaceutical compositions intended for combating diseases which cause demyelination.
According to one advantageous aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R1 is trifluoromethyl and Zxe2x80x2 and Zxe2x80x3 are hydrogen, or one of its pharmaceutically acceptable salts and solvates.
According to one preferred aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R1 is trifluoromethyl, Zxe2x80x2 and Zxe2x80x3 are hydrogen and Z is a 2-naphthyl, 6,7-dimethoxy-2-naphthyl or 6,7-methylenedioxy-2-naphthyl group, or one of its pharmaceutically acceptable salts and solvates.
According to another advantageous aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R1 is trifluoromethyl, Zxe2x80x2 and Zxe2x80x3 are hydrogen and Z is either a phenyl radical monosubstituted by a substituent X, X being:
(a) a (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)carboxyalkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C7)carboxyalkoxy or (C1-C4)alkoxycarbonyl(C1-C6)alkoxy group;
(b) a group selected from (C3-C7)cycloalkyl, (C3-C7)cycloalkoxy, (C3-C7)cycloalkylmethyl, (C3-C7)cycloalkylamino and cyclohexenyl, it being possible for said group to be substituted by a halogen, hydroxyl, (C1-C4)alkoxy, carboxyl, (C1-C4)alkoxycarbonyl, amino or mono- or di-(C1-C4)alkylamino; or
(c) a group selected from phenyl, phenoxy, phenylamino, Nxe2x80x94(C1-C3)alkyl-phenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, it being possible for said group to be monosubstituted or polysubstituted on the phenyl group by a halogen, CF3, (C1-C4)alkyl, (C1-C4)alkoxy, cyano, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)acylamino, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4)alkylaminocarbonyl, amino(C1-C4)alkyl, hydroxy(C1-C4)alkyl or halogeno(C1-C4)alkyl;
or a phenyl disubstituted by R2 and X as defined above, or one of its pharmaceutically acceptable salts and solvates.
According to another advantageous aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R1 is trifluoromethyl, Zxe2x80x2 and Zxe2x80x3 are hydrogen and Z is either a phenyl monosubstituted by a group Xxe2x80x2, Xxe2x80x2 being a phenyl which is unsubstituted or monosubstituted to trisubstituted by halogen, CF3, (C1-C4)alkyl, (C1-C4)alkoxy, cyano, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)acylamino, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4)alkylaminocarbonyl, amino(C1-C4)alkyl, hydroxy(C1-C4)alkyl or halogeno(C1-C4)alkyl; or a phenyl substituted by a substituent R2, R2 being a halogen or a hydroxyl, methyl, ethyl, (C3-C6)alkyl, (C1-C4)alkoxy or trifluoromethyl group, and by a substituent Xxe2x80x2, Xxe2x80x2 being as defined above, or one of its pharmaceutically acceptable salts and solvates.
According to another advantageous aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R1 is trifluoromethyl, Zxe2x80x2 and Zxe2x80x3 are hydrogen and Z is a phenyl group substituted in the 3- and 4-positions by a (C1-C6)alkyl group, or one of its pharmaceutically acceptable salts and solvates.
According to another advantageous aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R1 is trifluoromethyl, Zxe2x80x3 is hydrogen and Z and Zxe2x80x2, which are identical, are each a phenyl group; a phenyl group substituted in the 2-, 3- or 4-position by a fluorine or chlorine atom or by a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, cyano, methoxy, methylthio, methylsulfonyl, ethoxy, ethylthio, ethylsulfonyl, (C1-C3)alkoxycarbonyl or di(C1-C3)alkylaminocarbonyl group; a phenyl group disubstituted in the 2,4-, 3,4-, 3,5- or 2,6-positions by a chlorine or fluorine atom or by a methyl, ethyl, trifluoromethyl, cyano or methoxy group; or a phenyl group trisubstituted in the 3,4,5-, 2,4,5- or 2,4,6-positions by a chlorine or fluorine atom or by a methyl, ethyl, trifluoromethyl, cyano or methoxy group, or one of its pharmaceutically acceptable salts and solvates.
Particularly advantageous compounds according to the present invention are the following compounds:
1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(6,7-dimethoxynaphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(6,7-methylenedioxynaphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[(2S)-2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[(2R)-2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-isobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-tert-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-isobutylphenyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-isopropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(2xe2x80x2-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-fluorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2-trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-cyclohexylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(biphenyl-4-yl)ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(biphenyl-4-yl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-phenoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-benzylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-n-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(biphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-n-butoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3,4-diethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3-methyl-4-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-methyl-3-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3,4-diethylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;
1-(2,2-diphenylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2,2-(4,4xe2x80x2-dichlorodiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2,2-(3,3xe2x80x2-bistrifluoromethyldiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2,2-(4,4xe2x80x2-dimethoxydiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-fluorophenyl)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-(3,3-diphenylpropyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2,2-(4,4xe2x80x2-dichlorodiphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(2xe2x80x2-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-isobutylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-benzylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-cyclohexylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-fluorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-n-butylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(biphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-t-butylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1 ,2,3,6-tetrahydropyridine;
1-[2-(2,3xe2x80x2-dichlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2,5xe2x80x2-dichlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(2xe2x80x2,4xe2x80x2-dichlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(2-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2-chlorobiphenyl-4-yl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(2-fluorobiphenyl-4-yl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-methoxybiphenyl-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-methoxybiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-hydroxybiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4xe2x80x2-ethoxycarbonylbutoxybiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(biphenyl-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2-chloro-4xe2x80x2-fluorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(2xe2x80x2-trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3,4-diisobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3,4-dipropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-cyclohexylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;
1-[2-(4-isobutylphenyl)propyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;
1-[2-(2xe2x80x2-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
1-[2-(3xe2x80x2-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;
and their pharmaceutically acceptable salts and solvates.
1-(2-Naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and its pharmaceutically acceptable salts and solvates, especially its hydrochloride, are particularly preferred compounds for the use according to the present invention.
The compounds of formula (I) in which Zxe2x80x2 and Zxe2x80x3 are hydrogen are prepared as described in WO 97/01536.
The compounds of formula (I) in which one of Zxe2x80x2 and Zxe2x80x3 is hydrogen and the other is a hydroxyl, and the compounds in which Zxe2x80x2 and Zxe2x80x3 together are an oxo group, can be prepared as described in WO 93/11107.
The compounds of formula (I) in which Zxe2x80x3 is hydrogen and Z and Zxe2x80x2 are each independently an unsubstituted or mono-, di- or tri-substituted phenyl group are prepared by the following process:
(a) an aryl-1,2,3,6-tetrahydropyridine of formula (II): 
xe2x80x83in which Y and R1 are as defined above, is reacted with an acid of formula (III): 
xe2x80x83in which Z and Zxe2x80x2 are as defined above, or one of its functional derivatives,
(b) the intermediate carbonyl of formula (IV): 
xe2x80x83is reduced and
(c) the resulting compound of formula (I) is isolated and optionally converted to one of its salts or solvates.
The reaction of step (a) can be conveniently carried out in an organic solvent at a temperature between xe2x88x9210xc2x0 C. and the reflux temperature of the reaction mixture; the reaction is preferably carried out at low temperature.
The reaction solvent used is preferably a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform or the like, or an alcohol such as methanol or ethanol, but it is also possible to use other organic solvents compatible with the reactants employed, for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane.
The reaction can be conveniently carried out in the presence of a proton acceptor, for example an alkali metal carbonate or a tertiary amine. As the appropriate functional derivative of the acid of formula (III), it is possible to use the free acid, which may be activated (for example with BOP), the anhydride, a mixed anhydride, an activated ester or an acid halide, preferably the chloride or bromide. Among the activated esters, the p-nitrophenyl ester is particularly preferred, but the methoxyphenyl, trityl, benzhydryl and similar esters are also convenient.
The reduction of step (b) can be conveniently carried out with appropriate reducing agents such as aluminum hydrides or lithium aluminum hydride, in an inert organic solvent, at a temperature between 0xc2x0 C. and the reflux temperature of the reaction mixture, by the customary techniques. xe2x80x9cInert organic solventxe2x80x9d is understood as meaning a solvent which does not interfere with the reaction. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane.
The compound of formula (I) obtained is isolated by the customary techniques and optionally converted to one of its acid addition salts or, if an acid group is present, the amphoteric character of the compound permits separation of the salts with either acids or bases.
The starting amines of formula (II) in which Y is CH are known compounds or they can be prepared by processes analogous to those used for preparing the known compounds.
The starting amines of formula (II) in which Y is N can be prepared by reacting the appropriate 2-halogenopyridine of formula (p): 
in which R1 is as defined above and Hal is a halogen atom, with a 1,2,3,6-tetra-hydropyridine of formula (q): 
in which Pxc2x0 is a protecting group, for example the benzyl group, and Z is a substituent which permits nucleophilic substitution of the pyridine halogen. Examples of such substituents are trialkylstannanes, like tributylstannane, or Grignard compounds.
The 1,2,3,6-tetrahydropyridine is then deprotected by cleaving the protecting group under suitable conditions.
The acids of formula (III) can be prepared by a Wittig reaction in which:
an appropriate benzophenone of formula (r): 
xe2x80x83in which Z and Zxe2x80x2 are as defined above, is reacted with trimethylsulfoxonium iodide/BF3-Et2O and the intermediate aldehyde of formula (w): 
xe2x80x83is oxidized by the method described in J. Am. Chem. Soc., 1990, 112(18), 6690-6695, to give the corresponding acid.
In another procedure, the compounds of formula (I) in which Zxe2x80x3 is hydrogen can also be prepared by reacting an aryl-1,2,3,6-tetrahydropyridine of formula (II): 
in which R1 and Y are as defined above, with an aldehyde of formula (w) above, in the presence of a reducing agent such as sodium cyanoborohydride, by the known techniques.
The compounds of formula (I) in which R1 is m-trifluoromethyl, Y is CH, Zxe2x80x2 and Zxe2x80x3 are hydrogen and Z is a naphthyl group substituted by one or two alkoxy groups or by a methylenedioxy group are prepared as described in EP 0 458 697.
1-(2-Naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and its pharmaceutically acceptable salts and solvates, especially the hydrochloride, can be prepared according to EP 0 101 381.
In an advantageous method, 2-(2-bromoethyl)naphthalene is reacted with 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and, preferably, 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride is isolated; this is subsequently crystallized from an ethanol/water mixture by heating and cooling to 5xc2x0 C. at a rate of 10xc2x0 C./hour and with a stirrer speed of 400 rpm to give a mixture of two crystalline forms in a ratio of about 66/34.
1-(2-Naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride is preferably used in microparticulate form, for example in an essentially amorphous form obtained by atomization or in a microcrystalline form obtained by micronization.
The activity of the compounds of formula (I) was investigated in the model of experimental allergic encephalitis (EAE) induced in Lewis rats by the intraplantar administration of myelin basic protein (MBP) (fragment 68-84) in a Freund""s complete adjuvant (FCA) enriched in Mycobacterium tuberculosis, according to the protocol published by Martin and Near (Journal of Neuroimmunology, 1995, 241-245).
EAE is an inflammatory autoimmune disease of the central nervous system which presents demyelinating lesions reminiscent of human multiple sclerosis.
In this experimental model, representative compounds according to the invention, administered orally from day zero of induction of the disease, very significantly alleviate the disease as measured both by the variations in weight of the animals (the diseased animals present a large weight loss) and by the severity of the pathological condition (the diseased animals present paralysis of the back paws). The weight loss of the treated animals, especially those treated with 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, is significantly lower than that of the animals treated with the vehicle only. Likewise, the disease is statistically less severe in the groups of animals treated with 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride.
Another recognized major event in multiple sclerosis is the loss of integrity of the blood-brain barrier under attack of the immune system. This pathological effect is also demonstrated in the EAE model.
It was verified that the degradation of the blood-brain barrier is substantially reduced, or even non-existent (the barrier presenting no permeability anomaly), in the animals treated with representative compounds of the invention, compared with the control animals.
The results of these studies show that the compounds of formula (I), especially 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and its pharmaceutically acceptable salts and solvates, have a favorable action in this pathological condition of neurological dysfunction and can thus be clinically applied in the treatment of diseases which cause demyelinating lesions, such as multiple sclerosis.
The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are preferably administered orally.
In the pharmaceutical compositions of the present invention for oral administration, the active principle can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the treatment of the above-mentioned complaints. The appropriate unit forms of administration include for example tablets, which may be divisible, gelatin capsules, powders, granules and solutions or suspensions to be taken orally.
When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or the like. The tablets can be coated with sucrose or other appropriate substances, or else they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir can contain the active ingredient together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, a flavoring and an appropriate color.
The water-dispersible powders or granules can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
The active principle can also be formulated as microcapsules, optionally with one or more carriers or additives.
In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
The amount of active principle to be administered depends, as always, on how advanced the disease is and on the patient""s age and weight. Nevertheless the unit doses generally comprise from 0.1 to 100 mg, preferably from 0.25 to 50 mg and particularly preferably from 0.5 to 20 mg of active principle.
The preferred compound for the use according to the present invention, i.e. 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride in microparticulate form, is used in unit doses of 0.5 to 10 mg, advantageously of 1 to 5 and preferably of 1 to 3 mg, for example 1, 1.5, 2, 2.5 or 3 mg, of active principle. These unit doses are normally administered one or more times a day, preferably one to three times a day, the overall dose in humans varying between 0.5 and 50 mg per day, for example from 1 to 20 mg per day and advantageously from 2 to 10 mg per day.
According to another of its aspects, the present invention relates to a synergistic association comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and at least one compound selected from immunosuppressants such as interferon xcex2-1b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; and interleukin-1 inhibitors.
More particularly, the invention relates to an association comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and at least one compound selected from roquinimex (1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-3-quinolinecarboxanilide), myloran (a product from Autoimmune containing bovine myelin), antegren (a monoclonal human antibody from Elan/Athena Neurosciences) and recombinant interferon xcex2-1a.
Other possible associations are those consisting of a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and a potassium channel blocker, for example fampridine (4-aminopyridine).
According to another aspect, the present invention relates to a method of treating diseases which cause demyelination, comprising the administration, to a subject in need thereof, of an effective amount of a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates.
According to another aspect, the present invention relates to a method of treating diseases which cause demyelination, comprising the administration, to a subject in need thereof, of an effective amount of an association comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and at least one compound selected from immunosuppressants such as interferon xcex2-1b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; and interleukin-1 inhibitors.
The Examples which follow illustrate the invention more clearly without however implying a limitation.